JPWO2021081225A5 - - Google Patents
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- JPWO2021081225A5 JPWO2021081225A5 JP2022523854A JP2022523854A JPWO2021081225A5 JP WO2021081225 A5 JPWO2021081225 A5 JP WO2021081225A5 JP 2022523854 A JP2022523854 A JP 2022523854A JP 2022523854 A JP2022523854 A JP 2022523854A JP WO2021081225 A5 JPWO2021081225 A5 JP WO2021081225A5
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- polynucleotide construct
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Description
[本発明1001]
5'から3'に向かって、
(a) SEQ ID NO: 2の配列を含む5' UTR；
(b) 機能的なヒトオルニチントランスカルバミラーゼ（OTC）をコードするオープンリーディングフレーム（ORF）を含むmRNA配列であって、ORFが、SEQ ID NO: 1と少なくとも約95%同一であるコドン最適化された配列を含む、該mRNA配列；および
(c) SEQ ID NO: 3の配列を含む3' UTR
を含む、ポリヌクレオチド構築物。
[本発明1002]
機能的なヒトオルニチントランスカルバミラーゼ（OTC）をコードするオープンリーディングフレーム（ORF）を含むmRNA配列を含むポリヌクレオチド構築物であって、該mRNA配列が、SEQ ID NO: 4とは異なる5個以下の核酸を有する配列を含む、該ポリヌクレオチド構築物。
[本発明1003]
5'から3'に向かって、
(a) 5' UTR；
(b) 前記OTCをコードするORFを含むmRNA配列；および
(c) 3' UTR
を含む、本発明1002のポリヌクレオチド構築物。
[本発明1004]
前記5' UTRがSEQ ID NO: 2の配列を含む、本発明1003のポリヌクレオチド構築物。
[本発明1005]
前記3' UTRがSEQ ID NO: 3の配列を含む、本発明1003または1004のポリヌクレオチド構築物。
[本発明1006]
前記機能的なOTCがSEQ ID NO: 7のアミノ酸配列を含む、本発明1001～1005のいずれかのポリヌクレオチド構築物。
[本発明1007]
OFR配列がSEQ ID NO: 1を含む、本発明1001～1006のいずれかのポリヌクレオチド構築物。
[本発明1008]
前記mRNA配列が、SEQ ID NO: 4とは異なる4個以下、3個以下、2個以下、または1個以下の核酸を有する、本発明1001～1007のいずれかのポリヌクレオチド構築物。
[本発明1009]
SEQ ID NO: 4の配列を含む、本発明1001～1008のいずれかのポリヌクレオチド構築物。
[本発明1010]
5'末端キャップをさらに含む、本発明1001～1009のいずれかのポリヌクレオチド構築物。
[本発明1011]
前記5'末端キャップがCap1である、本発明1010のポリヌクレオチド構築物。
[本発明1012]
ポリAテールをさらに含む、本発明1001～1011のいずれかのポリヌクレオチド構築物。
[本発明1013]
前記ポリAテールが核酸80～1000個の長さである、本発明1012のポリヌクレオチド構築物。
[本発明1014]
前記ポリAテールが核酸100～500個の長さである、本発明1012のポリヌクレオチド構築物。
[本発明1015]
前記mRNAが、少なくとも1つの化学修飾ウリジンを含む、本発明1001～1014のいずれかのポリヌクレオチド構築物。
[本発明1016]
前記ウリジンの少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、または約100%が化学修飾されている、本発明1015のポリヌクレオチド構築物。
[本発明1017]
前記化学修飾ウリジンが、シュードウリジン（Ψ）、N1-メチルシュードウリジン（N1-me-Ψ）、およびそれらの組み合わせからなる群より選択される、本発明1015または1016のポリヌクレオチド構築物。
[本発明1018]
(a) 本発明1001～1017のいずれかのポリヌクレオチド構築物；および
(b) 送達作用物質
を含む、組成物。
[本発明1019]
前記送達作用物質が、脂質ナノ粒子（LNP）、リポソーム、重合体、ミセル、プラスミド、ウイルス、またはそれらの任意の組み合わせを含む、本発明1018の組成物。
[本発明1020]
前記LNPが、PEG2000-C-DMA：13-B43：コレステロール：DSPC、PEG2000-S：13-B43：コレステロール：DSPC、PEG2000-S：18-B6：コレステロール：DSPC、およびPEG750-C-DLA：18-B6：コレステロール：DSPCからなる群より選択される、本発明1019の組成物。
[本発明1021]
前記ポリヌクレオチド構築物が前記LNP中に封入されている、本発明1019または1020の組成物。
[本発明1022]
前記ポリヌクレオチド構築物が前記LNP中に完全に封入されている、本発明1021の組成物。
[本発明1023]
前記ポリヌクレオチド構築物の少なくとも95%が前記LNP中に封入されている、本発明1022の組成物。
[本発明1024]
薬学的に許容される担体をさらに含む、本発明1018～1023のいずれかの組成物。
[本発明1025]
細胞においてOTCの発現量を増加させるための方法であって、
該細胞に、本発明1001～1017のいずれかのポリヌクレオチド構築物を含む組成物、または本発明1018～1024のいずれかの組成物を投与する段階を含む、該方法。
[本発明1026]
前記細胞が肝細胞である、本発明1025の方法。
[本発明1027]
オルニチントランスカルバミラーゼ欠損症（OTCD）に関連する症状を処置するかまたは低減させるための方法であって、
それを必要とする対象に、治療的有効量の、本発明1001～1017のいずれかのポリヌクレオチド構築物を含む組成物、または本発明1018～1024のいずれかの組成物を投与する段階を含む、該方法。
[本発明1028]
OTCDを有する対象において高アンモニア血症を処置するかまたは高アンモニア血症のリスクを低下させるための方法であって、
それを必要とする対象に、治療的有効量の、本発明1001～1017のいずれかのポリヌクレオチド構築物を含む組成物、または本発明1018～1024のいずれかの組成物を投与する段階を含む、該方法。
[本発明1029]
SEQ ID NO: 8に対して少なくとも85%、少なくとも90%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%、または100%の配列同一性を有する配列を含む、発現カセット。
[本発明1030]
プロモーターをさらに含む、本発明1029の発現カセット。
[本発明1031]
前記プロモーターがT7プロモーターである、本発明1030の発現カセット。
[本発明1032]
本発明1029～1031のいずれかの発現カセットを含む、プラスミド。
[本発明1033]
本発明1029～1031のいずれかの発現カセットを含むかまたは本発明1032のプラスミドを含む、宿主細胞。
[本発明1034]
それを必要とする対象においてOTCDを処置するための医薬を製造するための、本発明1001～1017のいずれかのポリヌクレオチド構築物または本発明1018～1024のいずれかの組成物または本発明1029～1031のいずれかの発現カセットまたは本発明1032のプラスミドまたは本発明1033の宿主細胞の使用。
[本発明1035]
OTCDを有する対象において高アンモニア血症を処置するかまたは高アンモニア血症のリスクを低下させるための医薬を製造するための、本発明1001～1017のいずれかのポリヌクレオチド構築物または本発明1018～1024のいずれかの組成物または本発明1029～1031のいずれかの発現カセットまたは本発明1032のプラスミドまたは本発明1033の宿主細胞の使用。
[本発明1036]
核酸のインビボ送達のための方法であって、
哺乳動物対象に、本発明1001～1017のいずれかのポリヌクレオチド構築物または本発明1018～1024のいずれかの組成物または本発明1029～1031のいずれかの発現カセットまたは本発明1032のプラスミドまたは本発明1033の宿主細胞を投与する段階を含む、該方法。
[本発明1037]
それを必要とする哺乳動物対象において疾患または異常を処置するための方法であって、
該哺乳動物対象に、治療的有効量の、本発明1001～1017のいずれかのポリヌクレオチド構築物または本発明1018～1024のいずれかの組成物または本発明1029～1031のいずれかの発現カセットまたは本発明1032のプラスミドまたは本発明1033の宿主細胞を投与する段階を含む、該方法。
[本発明1038]
前記疾患または異常が尿素サイクル異常症である、本発明1037の方法。
これらの局面および他の局面は、以下の詳細な説明を読むことにより明らかとなるであろう。
[Invention 1001]
From 5' to 3',
(a) 5' UTR containing the sequence of SEQ ID NO: 2;
(b) a codon-optimized mRNA sequence comprising an open reading frame (ORF) encoding a functional human ornithine transcarbamylase (OTC), the ORF being at least about 95% identical to SEQ ID NO: 1; said mRNA sequence, comprising a sequence of
(c) 3' UTR containing the sequence of SEQ ID NO: 3
A polynucleotide construct comprising.
[Present invention 1002]
A polynucleotide construct comprising an mRNA sequence containing an open reading frame (ORF) encoding a functional human ornithine transcarbamylase (OTC), the mRNA sequence having no more than 5 differences from SEQ ID NO: 4. The polynucleotide construct comprises a sequence having a nucleic acid.
[Present invention 1003]
From 5' to 3',
(a) 5'UTR;
(b) an mRNA sequence comprising an ORF encoding said OTC; and
(c) 3' UTR
A polynucleotide construct of the invention 1002, comprising:
[Present invention 1004]
The polynucleotide construct of the invention 1003, wherein said 5' UTR comprises the sequence of SEQ ID NO: 2.
[Present invention 1005]
The polynucleotide construct of the invention 1003 or 1004, wherein said 3' UTR comprises the sequence of SEQ ID NO: 3.
[Present invention 1006]
The polynucleotide construct of any of the invention 1001-1005, wherein said functional OTC comprises the amino acid sequence of SEQ ID NO: 7.
[Present invention 1007]
The polynucleotide construct of any of the invention 1001-1006, wherein the OFR sequence comprises SEQ ID NO: 1.
[Present invention 1008]
The polynucleotide construct of any of the inventions 1001-1007, wherein the mRNA sequence has no more than 4, no more than 3, no more than 2, or no more than 1 nucleic acid different from SEQ ID NO: 4.
[Present invention 1009]
A polynucleotide construct according to any of the invention 1001-1008, comprising the sequence of SEQ ID NO: 4.
[Present invention 1010]
The polynucleotide construct of any of the invention 1001-1009, further comprising a 5' terminal cap.
[Present invention 1011]
The polynucleotide construct of the invention 1010, wherein said 5' end cap is Cap1.
[Invention 1012]
The polynucleotide construct of any of the invention 1001-1011, further comprising a polyA tail.
[Present invention 1013]
The polynucleotide construct of the invention 1012, wherein said polyA tail is 80 to 1000 nucleic acids long.
[Present invention 1014]
The polynucleotide construct of the invention 1012, wherein said polyA tail is 100 to 500 nucleic acids long.
[Present invention 1015]
The polynucleotide construct of any of the inventions 1001-1014, wherein said mRNA comprises at least one chemically modified uridine.
[Invention 1016]
at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% of the uridine is chemically modified. Polynucleotide construct of invention 1015.
[Invention 1017]
The polynucleotide construct of the invention 1015 or 1016, wherein said chemically modified uridine is selected from the group consisting of pseudouridine (Ψ), N1-methylpseudouridine (N1-me-Ψ), and combinations thereof.
[Invention 1018]
(a) the polynucleotide construct of any of the invention 1001 to 1017; and
(b) delivery agent;
A composition comprising.
[Invention 1019]
The composition of the invention 1018, wherein the delivery agent comprises a lipid nanoparticle (LNP), liposome, polymer, micelle, plasmid, virus, or any combination thereof.
[Invention 1020]
The LNP is PEG2000-C-DMA:13-B43:cholesterol:DSPC, PEG2000-S:13-B43:cholesterol:DSPC, PEG2000-S:18-B6:cholesterol:DSPC, and PEG750-C-DLA:18 -B6: Cholesterol: The composition of the present invention 1019 selected from the group consisting of DSPC.
[Invention 1021]
The composition of the invention 1019 or 1020, wherein said polynucleotide construct is encapsulated in said LNP.
[Invention 1022]
The composition of the invention 1021, wherein said polynucleotide construct is completely encapsulated within said LNP.
[Invention 1023]
The composition of the invention 1022, wherein at least 95% of said polynucleotide construct is encapsulated in said LNP.
[Invention 1024]
The composition of any of the inventions 1018-1023, further comprising a pharmaceutically acceptable carrier.
[Invention 1025]
A method for increasing the expression level of OTC in cells, the method comprising:
The method comprising administering to the cell a composition comprising a polynucleotide construct of any of the inventions 1001-1017 or a composition of any of the inventions 1018-1024.
[Invention 1026]
1025. The method of the invention 1025, wherein said cells are hepatocytes.
[Invention 1027]
A method for treating or reducing symptoms associated with ornithine transcarbamylase deficiency (OTCD), the method comprising:
administering to a subject in need thereof a therapeutically effective amount of a composition comprising a polynucleotide construct of any of the inventions 1001-1017, or a composition of any of the inventions 1018-1024. The method.
[Invention 1028]
A method for treating hyperammonemia or reducing the risk of hyperammonemia in a subject with OTCD, the method comprising:
administering to a subject in need thereof a therapeutically effective amount of a composition comprising a polynucleotide construct of any of the inventions 1001-1017, or a composition of any of the inventions 1018-1024. The method.
[Invention 1029]
SEQ ID NO: 8. cassette.
[Invention 1030]
The expression cassette of the invention 1029 further comprising a promoter.
[Present invention 1031]
The expression cassette of the present invention 1030, wherein the promoter is a T7 promoter.
[Invention 1032]
A plasmid comprising an expression cassette according to any one of the present invention 1029 to 1031.
[Present invention 1033]
A host cell comprising an expression cassette of any of the inventions 1029-1031 or comprising a plasmid of the invention 1032.
[Present invention 1034]
The polynucleotide construct of any of the inventions 1001-1017 or the composition of any of the inventions 1018-1024 or the invention 1029-1031 for the manufacture of a medicament for treating OTCD in a subject in need thereof Use of any of the expression cassettes or plasmids of the invention 1032 or host cells of the invention 1033.
[Invention 1035]
A polynucleotide construct of any of inventions 1001-1017 or inventions 1018-1024 for the manufacture of a medicament for treating hyperammonemia or reducing the risk of hyperammonemia in a subject with OTCD. or the expression cassette of any of the invention 1029-1031 or the plasmid of the invention 1032 or the host cell of the invention 1033.
[Invention 1036]
A method for in vivo delivery of nucleic acids, the method comprising:
A polynucleotide construct of any of the inventions 1001-1017 or a composition of any of the inventions 1018-1024 or an expression cassette of any of the inventions 1029-1031 or a plasmid of the invention 1032 or a plasmid of the invention in a mammalian subject. 1033 host cells.
[Present invention 1037]
A method for treating a disease or disorder in a mammalian subject in need thereof, the method comprising:
A therapeutically effective amount of the polynucleotide construct of any of the inventions 1001-1017 or the composition of any of the inventions 1018-1024 or the expression cassette or book of any of the inventions 1029-1031 is administered to the mammalian subject. The method comprising administering the plasmid of invention 1032 or the host cell of invention 1033.
[Invention 1038]
1037. The method of the invention 1037, wherein the disease or disorder is a urea cycle disorder.
These and other aspects will become apparent from reading the detailed description below.
Claims (35)
(a) SEQ ID NO: 2の配列を含む5' UTR；
(b) 機能的なヒトオルニチントランスカルバミラーゼ（OTC）をコードするオープンリーディングフレーム（ORF）を含むmRNA配列であって、ORFが、SEQ ID NO: 1と少なくとも約95%同一であるコドン最適化された配列を含む、該mRNA配列；および
(c) SEQ ID NO: 3の配列を含む3' UTR
を含む、ポリヌクレオチド構築物。 From 5' to 3',
(a) 5' UTR containing the sequence of SEQ ID NO: 2;
(b) a codon-optimized mRNA sequence comprising an open reading frame (ORF) encoding a functional human ornithine transcarbamylase (OTC), the ORF being at least about 95% identical to SEQ ID NO: 1; said mRNA sequence, comprising a sequence of
(c) 3' UTR containing the sequence of SEQ ID NO: 3
A polynucleotide construct comprising.
（i）SEQ ID NO: 2の配列を含む5' UTR、
（ii）機能的なヒトオルニチントランスカルバミラーゼ（OTC）をコードするオープンリーディングフレーム（ORF）を含むmRNA配列、および
（iii）SEQ ID NO: 3の配列を含む3' UTR
を含むポリヌクレオチド構築物であって、該mRNA配列が、SEQ ID NO: 4とは異なる5個以下の核酸を有する配列を含む、該ポリヌクレオチド構築物。 From 5' to 3',
(i) a 5' UTR containing the sequence of SEQ ID NO: 2;
(ii) an mRNA sequence containing an open reading frame (ORF) encoding a functional human ornithine transcarbamylase (OTC) ; and
(iii) 3' UTR containing the sequence of SEQ ID NO: 3
wherein the mRNA sequence comprises a sequence having five or fewer nucleic acids different from SEQ ID NO: 4.
(b) 送達作用物質
を含む、組成物。 (a) a polynucleotide construct according to any one of claims 1 to 14 ; and
(b) A composition comprising a delivery agent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962924567P | 2019-10-22 | 2019-10-22 | |
| US62/924,567 | 2019-10-22 | ||
| PCT/US2020/056890 WO2021081225A1 (en) | 2019-10-22 | 2020-10-22 | Ornithine transcarbamylase (otc) constructs and methods of using the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2022553375A JP2022553375A (en) | 2022-12-22 |
| JPWO2021081225A5 true JPWO2021081225A5 (en) | 2023-10-26 |
Family
ID=75620841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022523854A Pending JP2022553375A (en) | 2019-10-22 | 2020-10-22 | Ornithine transcarbamylase (OTC) constructs and methods of using same |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20230001021A1 (en) |
| EP (1) | EP4048317A4 (en) |
| JP (1) | JP2022553375A (en) |
| CN (1) | CN116096428A (en) |
| AU (1) | AU2020371697A1 (en) |
| CA (1) | CA3158626A1 (en) |
| IL (1) | IL292420A (en) |
| WO (1) | WO2021081225A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022512578A (en) | 2018-10-09 | 2022-02-07 | ザ ユニヴァーシティ オブ ブリティッシュ コロンビア | Compositions and systems comprising transfection competent vesicles free of organic solvents and no degradation agents and related methods. |
| WO2022229903A1 (en) * | 2021-04-28 | 2022-11-03 | Genevant Sciences Gmbh | Mrna delivery constructs and methods of using the same |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2919828C (en) * | 2013-07-30 | 2022-07-19 | Phaserx, Inc. | Block copolymers and their conjugates or complexes with oligonucleotides |
| JP2018509387A (en) * | 2015-01-21 | 2018-04-05 | フェーズアールエックス インコーポレイテッド | Methods, compositions, and systems for delivering therapeutic and diagnostic agents to cells |
| JP2019522047A (en) * | 2016-06-13 | 2019-08-08 | トランスレイト バイオ， インコーポレイテッド | Messenger RNA therapy for the treatment of ornithine transcarbamylase deficiency |
| US11938197B2 (en) * | 2017-01-10 | 2024-03-26 | The Sydney Children's Hospitals Network (Randwick And Westmead (Incorporating The Royal Alexandra Hospital For Children) | Polynucleotides and vectors for the expression of transgenes |
| EP3714048A1 (en) * | 2017-11-22 | 2020-09-30 | Modernatx, Inc. | Polynucleotides encoding ornithine transcarbamylase for the treatment of urea cycle disorders |
-
2020
- 2020-10-22 JP JP2022523854A patent/JP2022553375A/en active Pending
- 2020-10-22 AU AU2020371697A patent/AU2020371697A1/en active Pending
- 2020-10-22 EP EP20878326.6A patent/EP4048317A4/en active Pending
- 2020-10-22 US US17/771,421 patent/US20230001021A1/en active Pending
- 2020-10-22 CN CN202080089266.1A patent/CN116096428A/en active Pending
- 2020-10-22 WO PCT/US2020/056890 patent/WO2021081225A1/en unknown
- 2020-10-22 CA CA3158626A patent/CA3158626A1/en active Pending
- 2020-10-22 IL IL292420A patent/IL292420A/en unknown
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